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J Infect Dis. 2014 Aug 1;210(3):383-91. doi: 10.1093/infdis/jiu115. Epub 2014 Feb 28.

The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy.

Author information

1
Department of Epidemiology and Biostatistics, University of California, San Francisco Faculty of Medicine, Mbarara University of Science and Technology.
2
Faculty of Medicine, Mbarara University of Science and Technology Epicentre Mbarara research Base, Uganda.
3
Department of Bioengineering and Therapeutic Sciences.
4
Faculty of Medicine, Mbarara University of Science and Technology.
5
Department of Medicine, University of California, San Francisco.
6
Department of Epidemiology and Biostatistics, University of California, San Francisco.
7
California Department of Public Health, Richmond, CA.
8
Department of Medicine, Harvard Medical School Center for Global Health, Massachusetts General Hospital, Boston, MA.
9
Center for Global Health, Massachusetts General Hospital, Boston, MA Department of Global Health and Populations, Harvard School of Public Health Ragon Institute of MGH, MIT and Harvard.

Abstract

BACKGROUND:

Human immunodeficiency virus (HIV) infection-induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown.

METHODS:

We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the "KT ratio") in HIV-infected Ugandans before and during antiretroviral therapy (ART)-mediated viral suppression and its association with the rate of subsequent CD4(+) T-cell count recovery and mortality.

RESULTS:

Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4(+) T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4(+) T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4(+) T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4(+) T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P ≤ .016).

CONCLUSIONS:

The kynurenine pathway of tryptophan catabolism independently predicts poor CD4(+) T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.

KEYWORDS:

HIV; Tryptophan; Uganda; antiretroviral therapy; indoleamine 2,3-dioxygenase-1; kynurenine; mortality

PMID:
24585899
PMCID:
PMC4148610
DOI:
10.1093/infdis/jiu115
[Indexed for MEDLINE]
Free PMC Article
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